Protein kinases are a class of enzymes that catalyze the transfer of the γ-phosphate group from ATP to a recipient protein. The human genome is estimated to encode in excess of 500 distinct protein kinases, of which many have been implicated in a wide range of diseases and disorders, including cancer and inflammation.
The LIM kinases (LIMK) have been linked to the p53 pathway. See, e.g., International Application No. WO 02/099048. LIMK belongs to a small subfamily of kinases with a unique combination of two N-terminal LIM motifs and a C-terminal protein kinase domain. These LIM motifs and kinase domains are linked by a proline- and serine-rich region containing several putative casein kinase and map kinase recognition sites. LIM kinases and their pathway proteins are believed to contribute to Rho-induced reorganization of the actin cytoskeleton. Id. Members of the LIM kinase family include LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2). Both phosphorylate cofilin and regulates Rho family-dependent actin cytoskeletal rearrangement. Id.
LIM kinase inhibitors have been proposed for the treatment of cancer. Id. It has also been suggested that LIMK inhibitors may be useful in treating glaucoma by promoting actin depolymerization in trabecular cells and lowering ocular tension. See International Application No. WO 04/047868. Current glaucoma therapies operate by different mechanisms. Prostaglandin F2a analogues (e.g., latanoprost) effect an intraocular pressure (IOP) independent increase in fluid outflow from the eye. Carbonic anhydrous inhibitors (e.g., acetazolamide), beta-blockers (e.g., timolol), sympathomimetics (e.g., pilocarpine), and alpha adrenergic receptor agonists (e.g., brimonidine) decrease aqueous humor production.
An enormous number of compounds, with a wide variety of chemotypes, have been reported as kinase inhibitors. For example, phenyl-substituted pyrimidine compounds have been disclosed that are reportedly useful as LIMK inhibitors. See International Application WO 2006/084017. Pyrrole[2,3-d]pyrimidine-based compounds have been disclosed as inhibitors of various different kinases. See, e.g., U.S. patent publication no. 2004/0058922; International Application WO 2007/125325; International Application WO 2007/125321; International Application WO 2006/046024; U.S. patent publication no. 2005/0130954; and U.S. patent publication no. 2006/0189638.